COX/mPGES-1/PGE₂ pathway depicts an inflammatory-dependent high-risk neuroblastoma subset

The majority of solid tumors are presented with an inflammatory microenvironment. Proinflammatory lipid mediators including prostaglandin E ₂ (PGE ₂) contribute to the establishment of inflammation and have been linked to tumor growth and aggressiveness. Here we show that high-risk neuroblastoma...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2015, Vol.112 (26), p.8070-8075
Main Authors: Larsson, Karin, Anna Kock, Helena Idborg, Marie Arsenian Henriksson, Tommy Martinsson, John I. Johnsen, Marina Korotkova, Per Kogner, Per-Johan Jakobsson
Format: Article
Language:English
Subjects:
adulthood
angiogenesis
cancer-associated fibroblasts
childhood
chromosomes
fibroblasts
inflammation
metastasis
mPGES-1
neoplasms
neuroblastoma
PGE2
prognosis
prostaglandins
therapeutics
tumor microenvironment
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Summary:The majority of solid tumors are presented with an inflammatory microenvironment. Proinflammatory lipid mediators including prostaglandin E ₂ (PGE ₂) contribute to the establishment of inflammation and have been linked to tumor growth and aggressiveness. Here we show that high-risk neuroblastoma with deletion of chromosome 11q represents an inflammatory subset of neuroblastomas. Analysis of enzymes involved in the production of proinflammatory lipid mediators showed that 11q-deleted neuroblastoma tumors express high levels of microsomal prostaglandin E synthase-1 (mPGES-1) and elevated levels of PGE ₂. High mPGES-1 expression also corresponded to poor survival of neuroblastoma patients. Investigation of the tumor microenvironment showed high infiltration of tumor-promoting macrophages with high expression of the M2-polarization markers CD163 and CD206. mPGES-1–expressing cells in tumors from different subtypes of neuroblastoma showed differential expression of one or several cancer-associated fibroblast markers such as vimentin, fibroblast activation protein α, α smooth muscle actin, and PDGF receptor β. Importantly, inhibition of PGE ₂ production with diclofenac, a nonselective COX inhibitor, resulted in reduced tumor growth in an in vivo model of 11q-deleted neuroblastoma. Collectively, these results suggest that PGE ₂ is involved in the tumor microenvironment of specific neuroblastoma subgroups and indicate that therapeutic strategies using existing anti-inflammatory drugs in combination with current treatment should be considered for certain neuroblastomas. Significance Cancer-related inflammation promotes progression and therapy resistance in tumors of adulthood. Knowledge concerning the significance of inflammation in childhood malignancies has been limited. Neuroblastoma is an embryonal tumor of early childhood with poor prognosis despite intensified therapy, and biological understanding is necessary to develop novel therapies. We found high-risk neuroblastoma, in particular the therapy-resistant subset with chromosome 11q-deletion, to be inflammatory driven and characterized by high expression of the COX/microsomal prostaglandin E synthase-1 (mPGES-1)/prostaglandin E ₂ (PGE ₂) pathway that correlates with metastatic stage and poor clinical outcome. We further detected infiltrating cancer-associated fibroblasts expressing mPGES-1, the essential enzyme for synthesis of PGE ₂, promoting tumor growth, angiogenesis, and metastatic s
ISSN:0027-8424
1091-6490